Summary: CpG encoding synthetic oligodeoxynucleotides (CpG ODN) are a new and promising generation of immunomodulators. They are recognized by the mammalian immune system and elicit innate and adaptive immune responses, predominantly of a TH1 phenotype. Although the immunostimulatory properties of CpG DNA were only recently described, over a dozen clinical trials exploring their utility as vaccine adjuvants, immunotherapeutic agents, and anti-allergens have been initiated. As yet, however, there are no studies assessing the safety and effectiveness of CpG ODN in women. There are reasons to suspect that women will respond differently to CpG ODN than men do since female sex hormones, in general, promote B cell-mediated immunity while suppressing the Th1-type cellular immune responses that CpG ODN promote. Our studies, partly supported by a grant from the Offic of Women's Health, are focused on: (1) assessing CpG ODN response (induction of cytokine and Ig secretion, cell proliferation and cell surface expression of activation markers on antigen presenting cells) of immune cells treated in vitro and/or in vivo with increasing concentrations of sex hormones for various periods; (2)establishing whether sex hormones modify the efficacy of CpG ODN based immunotherapeutic agents in vivo. This is accomplished by using mouse models that are established in our laboratory in which CpG ODN have proven effective (Leishmania major for vaccine adjuvancy, and Listeria monocytogenes for immunoprotection studies), and (3) assessing the safety parameters of CpG ODN administration in females.